红花黄色素对高脂血症家兔抗动脉硬化的作用

Effect of safflower yellow on atherosclerosis in rabbits with hyperlipidemia

目的探讨注射用红花黄色素对高脂血症新西兰兔抗动脉硬化的作用。方法将96只新西兰兔随机分为4大组:正常对照组、模型组、受试红花黄色素3组(10.9、5.45和2.725 mg/kg)和阳性对照阿托伐他汀组,正常对照组给予普通饲料喂养,其余3组采用高脂饲料喂养联合维生素D3腹腔注射方法建立高脂血症模型,连续饲养8周。其后红花黄色素3个剂量受试组分别腹腔注射红花黄色素,1次/日,阳性对照阿托伐他汀组灌胃给予阿托伐他汀钙[2 mg/(kg·d)],正常对照组和模型组灌胃给予等剂量的生理盐水,连续给药8周。末次给药禁食16 h后,检测兔体质量、血清总胆固醇(TC)、甘油三酯(TG)、低密度脂蛋白胆固醇(LDL-C)、高密度脂蛋白胆固醇(HDL-C)、氧化型低密度脂蛋白(OX-LDL),主动脉基质金属蛋白酶-9(MMP-9)和基质金属蛋白酶抑制因子-1(TIMP-1),肝中载脂蛋白E(ApoE)、低密度脂蛋白受体(LDL-R)和B类Ⅰ型清道夫受体(SR-B1),以及血清中缺氧诱导因子1α(HIF-1α)、血管内皮生长因子(VEGF)、血管内皮细胞黏附分子-1(VCAM-1)、血小板因子4(PF4)的水平,HE染色观察胸主动脉组织病理学形态变化。结果建模第16周,与正常对照组比较,模型组兔体质量、血清TC、TG、LDL-C、OX-LDL、HIF-1α、VEGF、VCAM-1和PF4表达明显升高(P<0.05);主动脉MMP-9水平也明显升高(P<0.05),TIMP-1水平显著降低(P<0.05);血清HDL-C、肝中ApoE、LDL-R和SR-B1水平明显降低(P<0.05);HE染色见模型组胸主动脉出现动脉粥样硬化改变。与模型组比较,红花黄色素3个剂量组兔的体质量、血清TC、LDL-C、OX-LDL、HIF-1α、VEGF、VCAM-1和PF4,以及主动脉MMP-9水平均显著降低(P<0.05),TIMP-1水平均明显升高(P<0.05);红花黄色素10.9和5.45 mg/kg剂量组兔血清TG水平均降低(P<0.05),肝中ApoE、SR-B1水平明显升高(P<0.05);红花黄色素10.9 mg/kg剂量组兔肝中LDL-R水平明显升高(P<0.05);HE染色见红花黄色素组胸主动脉动脉粥样硬化明显减轻。结论红花黄色素可能通过调控脂质代谢和肝中MMP-9/肝中TIMP-1平衡,并抑制血清HIF-1α、VEGF、VCAM-1、PF4表达,从而抑制动脉粥样硬化的进展。

Objective To investigate the effect of safflower yellow injection on atherosclerosis in rabbits with hyperlipidemia.Methods Ninety-six New Zealand rabbits were randomly divided into four groups:the control group,model group,safflower yellowtest group(10.9,5.45 and 2.725 mg/kg)and the positive control(atorvastatin)group. The control group was fed with normal feed,while the other three groups were fed with high fat diet for 8 weeks,combined with intraperitoneal injection of vitamin D3,to establish hyperlipidemia model. Then,the three-dosage safflower yellow-test groups were given intraperitoneal injection of safflower yellow(10.9,5.45 and 2.725 mg/kg),respectively,the positive control group was given atorvastatin calcium[2 mg/(kg·d)]by intragastric administration,and the control and model groups were orally given an equal volume of normal saline,all once a day every day for 8weeks. After 16 h fasting following the last administration,the body weight,total cholesterol(TC),triglyceride(TG),low density lipoprotein cholesterol(LDL-C),high density lipoprotein cholesterol(HDL-C),oxidized low density lipoprotein(OX-LDL),matrix metalloproteinases 9(MMP-9),tissue inhibitors of metalloproteinase 1(TIMP-1),apolipoprotein E(ApoE),low density lipoprotein receptor(LDL-R),and scavenger receptor class B type1(SR-B1)levels were measured. The morphological changes of thoracic aortas were examined by HE staining. Results At the 16 th week,compared with the control group,the body weight as well as the TC,TG,LDL-C,OX-LDL,MMP-9,HIF-1α,VEGF,VCAM-1 and PF4 level were all increased significantly(P<0.05),while the level of HDL-C,ApoE,LDL-R,and SR-B1 decreased significantly(P<0.05),accompanied with the atherosclerotic changes in the thoracic aortas indicated by the HE staining in the model group. Compared with the model group,the body weight as well as the TC,LDL-C,OX-LDL,MMP-9,HIF-1α,VEGF,VCAM-1 and PF4 level were decreased significantly(P<0.05),and the TIMP-1 level increased(P<0.05)in all of the three-dosage safflower yellow-test groups. Meanwhile,compared with the model group,in the 10.9 and 5.45 mg/kg safflower yellow groups,the TG level were decreased and the ApoE and SR-B1 levels were increased significantly(P<0.05). On the other hand,the LDL-R level significantly increased only in the safflower yellow 10.9 mg/kg group(P<0.05). HE staining showed a significant reduction in atherosclerorotic changes of the thoracic aorta in the safflower yellow-test groups. Conclusion Safflower yellow may inhibit the progression of atherosclerosis by regulating the lipid metabolism and MMP-9/TIMP-1 balance and also by inhibiting the HIF-1α,VEGF,VCAM-1 and PF4 expression.